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Please use this identifier to cite or link to this item: http://hdl.handle.net/20.500.12128/8754
Title: Proline-based carbamates as cholinesterase inhibitors
Authors: Pizova, Hana
Havelkova, Marketa
Stepankova, Sarka
Bąk, Andrzej
Kauerova, Tereza
Kozik, Violetta
Oravec, Michal
Imramovsky, Ales
Kollar, Peter
Bobal, Pavel
Jampilek, Josef
Keywords: proline; carbamates; in vitro cholinesterase inhibition; in vitro cytotoxicity assay; CoMSA; IVE-PLS; molecular docking study
Issue Date: 2017
Citation: Molecules (Basel), 2017, iss. 11, art. no 1969
Abstract: Series of twenty-five benzyl (2S)-2-(arylcarbamoyl)pyrrolidine-1-carboxylates was prepared and completely characterized. All the compounds were tested for their in vitro ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), and the selectivity of compounds to individual cholinesterases was determined. Screening of the cytotoxicity of all the compounds was performed using a human monocytic leukaemia THP-1 cell line, and the compounds demonstrated insignificant toxicity. All the compounds showed rather moderate inhibitory effect against AChE; benzyl (2S)-2-[(2-chlorophenyl)carbamoyl]pyrrolidine-1-carboxylate (IC50 = 46.35 M) was the most potent agent. On the other hand, benzyl (2S)-2-[(4-bromophenyl)-] and benzyl (2S)-2-[(2-bromophenyl)carbamoyl]pyrrolidine-1-carboxylates expressed anti-BChE activity (IC50 = 28.21 and 27.38 M, respectively) comparable with that of rivastigmine. The ortho-brominated compound as well as benzyl (2S)-2-[(2-hydroxyphenyl)carbamoyl]pyrrolidine-1-carboxylate demonstrated greater selectivity to BChE. The in silico characterization of the structure–inhibitory potency for the set of proline-based carbamates considering electronic, steric and lipophilic properties was provided using comparative molecular surface analysis (CoMSA) and principal component analysis (PCA). Moreover, the systematic space inspection with splitting data into the training/test subset was performed to monitor the statistical estimators performance in the effort to map the probability-guided pharmacophore pattern. The comprehensive screening of the AChE/BChE profile revealed potentially relevant structural and physicochemical features that might be essential for mapping of the carbamates inhibition efficiency indicating qualitative variations exerted on the reaction site by the substituent in the 30-/40-position of the phenyl ring. In addition, the investigation was completed by a molecular docking study of recombinant human AChE.
URI: http://hdl.handle.net/20.500.12128/8754
DOI: 10.3390/molecules22111969
ISSN: 1420-3049
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